The genetic architecture of Parkinson's disease in Mexico: a systematic review

Despite substantial advances in Parkinson's disease genomics, Latin American populations remain underrepresented in global genetic studies, limiting the generalizability of risk estimates and biological inference. Mexico, characterized by complex admixture patterns, represents a critical setting for evaluating population-level genetic variation associated with Parkinson's disease.

Following PRISMA 2020 guidelines, we systematically reviewed original studies published between 2004 and February 2025 that investigated genetic variants or gene-expression profiles in clinically diagnosed Parkinson's disease among individuals recruited in Mexico. Twenty-four studies (7,048 participants; 3,367 patients and 3,781 controls) met the inclusion criteria. Variant nomenclature was harmonized using HGNC and dbSNP identifiers. Study quality was appraised using the Q-Genie instrument, and effect estimates were standardized where feasible. Functional interpretation incorporated Gene Ontology, WikiPathways, and network-based analyses.

Across the included literature, 27 genes and 71 distinct genetic variants were examined. Eight loci-PRKN, SNCA, GBA1, LRRK2, APOE, MTHFR, SYT11, and NR4A2-emerged as recurrently associated with Parkinson's disease. Biallelic PRKN variants and exon rearrangements predominated in early-onset disease, frequently co-occurring with PINK1 or LRRK2 alterations. The GBA1 p.L444P variant conferred increased risk, whereas the canonical LRRK2 p.G2019S mutation was consistently absent. Multiple regulatory SNCA polymorphisms showed consistent associations across the independent Mexican cohorts examined. Additional risk-modifying variants included APOE ε4, MTHFR rs1801133, and SYT11 variants rs34372695, rs729022, and rs822508. Protective associations were reported for NR4A2 haplotypes-distinguishing H1 as protective and H2 as risk-increasing-and for ALDH1A1 rs3764435. Functional integration highlighted convergence on mitochondrial quality control, lysosomal-autophagic processes, oxidative stress responses, synaptic vesicle cycling, and dopaminergic signaling.

This systematic review provides the first quality-assessed synthesis of genetic studies of Parkinson's disease conducted in Mexico. The available evidence supports the involvement of established Parkinson's disease-related molecular pathways while underscoring substantial methodological heterogeneity and limited ancestry-aware analyses. Larger, well-powered genome-wide and multi-omic studies incorporating explicit ancestry modeling are required to refine genetic risk architecture and improve the interpretability of Parkinson's disease genomics in Mexican populations.